Docosahexaenoic acid, or DHA, is a molecule of intense commercial interest of late due to emerging knowledge of its benefits in the treatment and prevention of cardiovascular and neurologic conditions, and the nutritional support and well-being of mothers and developing fetuses, among other health benefits. DHA is typically sold in bulk as an oil mixture that contains other polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA), although commercial sources of purified DHA, which have nominal amounts of EPA, have recently emerged.
The molecule has historically been derived from fish oil, but more recently algal oils have been isolated that are highly enriched in omega-3 fatty acids. In the case of certain fermentatively produced algae rich in omega-3 fatty acids (e.g., Crypthecodinium cohnii and Schizochytrium sp.), the process has been scaled up and commercialized. This process involves growing the algae, stressing the organisms to induce the production of an oil, harvesting and drying the algae, extracting the oil with an organic solvent, and purifying the oil using processes well known in the art for vegetable oil processing.
The DHA-enriched oils, whether derived from fish or algae, are not as stable as other vegetable oils such as corn oil, soybean oil, canola oil, palm oil, etc., because the DHA and other fatty acids are polyunsaturated and inherently susceptible to oxidative breakdown. Various attempts have been made to stabilize fish oils through the use of lipophilic antioxidants such as vitamin B, or by setting up a physical barrier between the fish oil and the food product matrix using encapsulation or coating.
Fully or partially refined marine oil has also been treated with silica and stabilized by incorporating a mixture of lecithin, ascorbyl palmitate, and alpha-tocopherol. See U.S. Pat. No. 5,855,944. Hamilton et al., J. Am. Oil Chem. Soc. (JAOCS) 75 (7), 813-822 (1998), disclose a ternary additive mixture (2% tocopherol, 0.1% ascorbyl palmitate, 0.5% lecithin) to prevent autoxidation of fish oils.
EP 340 635 describes a process of treating fish oils to increase their stability containing EPA and DHA by vacuum steam distillation under mild conditions to reduce low temperature boiling and less polar volatile flavor compounds, and subsequently contacting said oil with an adsorbent, e.g., silica gel, to reduce high temperature boiling and more polar volatile flavor compounds. The document also describes the combination of the purified oil with a rosemary extract antioxidant. US 2003/161918 A1 describes the preparation and stabilization of food-grade fish oils by treating a fish oil with silica, submitting it to a 2 hours batch vacuum steam deodorization in the presence of rosemary or sage extract and, if desired, adding ascorbyl palmitate and mixed tocopherol.
These methods, while successful, have been predominantly used to stabilize oils. To the inventors' knowledge, very little if any work has been done to stabilize polyunsaturated fatty acids, particularly DHA, when present in a dry admixture such as a tablet or powder-filled capsule. This may be because bulk DHA is practically always supplied in oil form in combination with other fatty acids, and practically always processed into liquid-filled gel-caps for eventual use by the consumer. While spray dry and encapsulation methods exist for manufacturing powdered forms of the molecule, to the inventors' knowledge, none of these powdered forms of DHA has been successfully processed, on a commercial scale, into a stable tablet or powder-filled capsule dosage form.
Various patents report having made tablets that contain polyunsaturated fatty acids. For example, U.S. Pat. No. 5,843,919 to Burger describes mixtures of glucosamine and EPA, and tablets that contain such mixtures. The document does not disclose any formulations for such tablets, and does not describe any methods for improving the stability of such tablets.
EP 342795 A2 to Taiyo describes compositions for improving cerebral function which contain DHA. Tablets are mentioned as a possible dosage form, without giving any specific formulation or any consideration to molecular stability. No consideration is given to tableting or powder-filled capsules where the fatty acid component is in the form of an oil.
WO 88/02221 by Kabivitrum describes an EPA/DHA granulate comprising an oil-powder mixture containing 2-75% vegetable oil and/or marine oil containing essential fatty acids selected from gamma linolenic acid (GLA), EPA and/or DHA and/or other marine oils and a water-soluble carrier, in combination with a solid pulverulent filler and a binder. The reference also states that tablets can be made from said granulate, and gives various excipients for use in making such tablets, including various conventional fillers, binders and additives such as vitamins and minerals. The document states that alpha tocopherol and ascorbyl palmitate can be added to the oil for protection against oxidation, but otherwise does not give meaningful consideration to the stability of the tablets or powder filled capsules or how to improve the stability.
U.S. Pat. No. 4,831,022 to Hijiya describes EPA inclusion complexes with gamma cyclodextrins with up to 47.6% EPA in the solid prepared. No consideration is given to tableting or the preparation of powder-filled capsules where the fatty acid component is in the form of an oil, or to the stability of such tablets or powder-filled capsules.
WO 2008/146016 by Campbell describes complexes of fatty acid esters and cyclodextrins that can be compressed into tablets with reportedly high concentrations of the fatty acid compound. The document reports that the complexes can be mixed with various excipients prior to compression into a tablet, including microcrystalline cellulose, stearic acid and colloidal silica. The document also reports that various drugs, vitamins and minerals can be mixed into the tablet, including simvastatin, vitamin C, calcium carbonate, folic acid, vitamin D3, vitamin K, and vitamin E. The document does not report any stability data for the various combinations, and uses mixtures of omega-3 fatty acids in the tablets rather than purified DHA.